Mechanistic DNA damage simulations in Geant4-DNA Part 2: Electron and proton damage in a bacterial cell

We extended a generic Geant4 application for mechanistic DNA damage simulations to an Escherichia coli cell geometry, finding electron damage yields and proton damage yields largely in line with experimental results. Depending on the simulation of radical scavenging, electrons double strand breaks (DSBs) yields range from 0.004 to 0.010 DSB Gy⁻¹ Mbp⁻¹, while protons have yields ranging from 0.004 DSB Gy⁻¹ Mbp⁻¹ at low LETs and with strict assumptions concerning scavenging, up to 0.020 DSB Gy⁻¹ Mbp⁻¹ at high LETs and when scavenging is weakest. Mechanistic DNA damage simulations can provide important limits on the extent to which physical processes can impact biology in low background experiments. We demonstrate the utility of these studies for low dose radiation biology calculating that in E. coli, the median rate at which the radiation background induces double strand breaks is 2.8 × 10⁻⁸ DSB day⁻¹, significantly less than the mutation rate per generation measured in E. coli, which is on the order of 10⁻³.     

Mechanistic DNA damage simulations in Geant4-DNA part 1: A parameter study in a simplified geometry

Mechanistic modelling of DNA damage in Monte Carlo simulations is highly sensitive to the parameters that define DNA damage. In this work, we use a simple testing geometry to investigate how different choices of physics models and damage model parameters can change the estimation of DNA damage in a mechanistic DNA damage simulation built in Geant4-DNA. The choice of physics model can lead to variations by up to a factor of two in the yield of physically induced strand breaks, and the parameters that determine scavenging, and physical and chemical single strand break induction can have even larger consequences. Using low energy electrons as primary particles, a variety of parameters are tested in this geometry in order to arrive at a parameter set consistent with past simulation studies. We find that the modelling of scavenging can play an important role in determining results, and speculate that high-scavenging regimes, where only chemical radicals within 1 nm of DNA are simulated, could provide a good means of testing mechanistic DNA simulations.     

Local dose enhancement of proton therapy by ceramic oxide nanoparticles investigated with Geant4 simulations

Nanoparticles (NPs) have been shown to enhance X-ray radiotherapy and proton therapy of cancer. The effectiveness of radiation damage is enhanced in the presence of high atomic number (high-Z) NPs due to increased production of low energy, higher linear energy transfer (LET) secondary electrons when NPs are selectively internalized by tumour cells. This work quantifies the local dose enhancement produced by the high-Z ceramic oxide NPs Ta₂O₅ and CeO₂, in the target tumour, for the first time in proton therapy, by means of Geant4 simulations. The dose enhancement produced by the ceramic oxides is compared against gold NPs. The energy deposition on a nanoscale around a single nanoparticle of 100 nm diameter is investigated using the Geant4-DNA extension to model particle interactions in the water medium. Enhancement of energy deposition in nano-sized shells of water, local to the NP boundary, ranging between 14% and 27% was observed for proton energies of 5 MeV and 50 MeV, depending on the NP material. Enhancement of electron production and energy deposition can be correlated to the direct DNA damage mechanism if the NP is in close proximity to the nucleus.     

Implementation of new physics models for low energy electrons in liquid water in Geant4-DNA

A new alternative set of elastic and inelastic cross sections has been added to the very low energy extension of the Geant4 Monte Carlo simulation toolkit, Geant4-DNA, for the simulation of electron interactions in liquid water. These cross sections have been obtained from the CPA100 Monte Carlo track structure code, which has been a reference in the microdosimetry community for many years. They are compared to the default Geant4-DNA cross sections and show better agreement with published data.In order to verify the correct implementation of the CPA100 cross section models in Geant4-DNA, simulations of the number of interactions and ranges were performed using Geant4-DNA with this new set of models, and the results were compared with corresponding results from the original CPA100 code. Good agreement is observed between the implementations, with relative differences lower than 1% regardless of the incident electron energy.Useful quantities related to the deposited energy at the scale of the cell or the organ of interest for internal dosimetry, like dose point kernels, are also calculated using these new physics models. They are compared with results obtained using the well-known Penelope Monte Carlo code.     

Geant4 implementation of inter-atomic interference effect in small-angle coherent X-ray scattering for materials of medical interest

An extension to Geant4 Monte Carlo code was developed to take into account inter-atomic (molecular) interference effects in X-ray coherent scattering. Based on our previous works, the developed code introduces a set of form factors including interference effects for a selected variety of amorphous materials useful for medical applications, namely various tissues and plastics used to build phantoms. The code is easily upgradable in order to include new materials and offers the possibility to model a generic tissue as a combination of a set of four basic components. A dedicated Geant4 application for the simulation of X-ray diffraction experiments was created to validate the proposed upgrade of Rayleigh scattering model. A preliminary validation of the code obtained through a comparison with EGS4 and an experiment is presented, showing a satisfactory agreement.     

Measurement of depth-dose of linear accelerator and simulation by use of Geant4 computer code

Radiation therapy is an established method of cancer treatment. New technologies in cancer radiotherapy need a more accurate computation of the dose delivered in the radiotherapy treatment plan. This study presents some results of a Geant4-based application for simulation of the absorbed dose distribution given by a medical linear accelerator (LINAC). The LINAC geometry is accurately described in the Monte Carlo code with use of the accelerator manufacturer''s specifications. The capability of the software for evaluating the dose distribution has been verified by comparisons with measurements in a water phantom; the comparisons were performed for percentage depth dose (PDD) and profiles for various field sizes and depths, for a 6-MV electron beam. Experimental and calculated dose values were in good agreement both in PDD and in transverse sections of the water phantom.     

A GATE/Geant4 beam model for the MedAustron non-isocentric proton treatment plans quality assurance

PurposeTo present a reference Monte Carlo (MC) beam model developed in GATE/Geant4 for the MedAustron fixed beam line. The proposed model includes an absolute dose calibration in Dose-Area-Product (DAP) and it has been validated within clinical tolerances for non-isocentric treatments as routinely performed at MedAustron.Material and MethodsThe proton beam model was parametrized at the nozzle entrance considering optic and energy properties of the pencil beam. The calibration in terms of absorbed dose to water was performed exploiting the relationship between number of particles and DAP by mean of a recent formalism. Typical longitudinal dose distribution parameters (range, distal penumbra and modulation) and transverse dose distribution parameters (spot sizes, field sizes and lateral penumbra) were evaluated. The model was validated in water, considering regular-shaped dose distribution as well as clinical plans delivered in non-isocentric conditions.ResultsSimulated parameters agree with measurements within the clinical requirements at different air gaps. The agreement of distal and longitudinal dose distribution parameters is mostly better than 1 mm. The dose difference in reference conditions and for 3D dose delivery in water is within 0.5% and 1.2%, respectively. Clinical plans were reproduced within 3%.ConclusionA full nozzle beam model for active scanning proton pencil beam is described using GATE/Geant4. Absolute dose calibration based on DAP formalism was implemented. The beam model is fully validated in water over a wide range of clinical scenarios and will be inserted as a reference tool for research and for independent dose calculation in the clinical routine.     

CPOP: An open source C++ cell POPulation modeler for radiation biology applications

PurposeMulticellular tumor spheroids are realistic in-vitro systems used in radiation biology research to study the effect of anticancer drugs or to evaluate the resistance of cancer cells under specific conditions. When combining the modeling of spheroids together with the simulation of radiation using Monte Carlo methods, one could estimate cell and DNA damage to be compared with experimental data. We developed a Cell Population (CPOP) modeler combined to Geant4 simulations in order to tackle how energy depositions are allocated to cells, especially when enhancing radiation outcomes using high-Z nanoparticles. CPOP manages to model large three-dimensional cell populations with independent deformable cells described with their nucleus, cytoplasm and membranes together with force law systems to manage cell–cell interactions.MethodsCPOP is an opensource platform written in C++. It is divided into two main libraries: a “Modeler” library, for cell geometry modeling using meshes, and a Multi Agent System (MAS) library, simulating all agent (cell) interactions among the population. CPOP is fully interfaced with the Geant4 Monte Carlo toolkit and is able to directly launch Geant4 simulations after compilation.We modeled a full and realistic 3D cell population from SK-MEL28 melanoma cell population cultured experimentally. The spheroid diameter of 550 ± 40 µm corresponds to a population of approximately 1000 cells having a diameter of 17.2 ± 2.5 µm and a nucleus diameter of 11.2 ± 2.0 µm. We decided to reproduce cell irradiations performed with a X-RAD 320 Biological Irradiator (Precision XRay Inc., North Branford, CT).ResultsWe simulated the energy spectrum of secondary particles generated in the vicinity of the spheroid and plotted the different energy spectra recovered internally to the spheroid. We evaluated also the impact of AGuIX (Gadolinium) nanoparticles modeled into the spheroid with their corresponding secondary energy spectra.ConclusionsWe succeeded into modeling cell populations and combined them with Geant4 simulations. The next step will be to integrate DNA geometrical models into cell nuclei and to use the Geant4-DNA physics and radiolysis modeling capabilities in order to evaluate early strand breaks induced on DNA.     

Neutron shielding for a new projected proton therapy facility: A Geant4 simulation study

In this work, we used the Monte Carlo-based Geant4 simulation toolkit to calculate the ambient dose equivalents due to the secondary neutron field produced in a new projected proton therapy facility. In particular the facility geometry was modeled in Geant4 based on the CAD design. Proton beams were originated with an energy of 250 MeV in the gantry rooms with different angles with respect to the patient; a fixed 250 MeV proton beam was also modeled. The ambient dose equivalent was calculated in several locations of interest inside and outside the facility, for different scenarios. The simulation results were compared qualitatively to previous work on an existing facility bearing some similarities with the design under study, showing that the ambient dose equivalent ranges obtained are reasonable. The ambient dose equivalents, calculated by means of the Geant4 simulation, were compared to the Australian regulatory limits and showed that the new facility will not pose health risks for the public or staff, with a maximum equivalent dose rate equal to 7.9 mSv/y in the control rooms and maze exit areas and 1.3·10⁻¹ mSv/y close to the walls, outside the facility, under very conservative assumptions. This work represents the first neutron shielding verification analysis of a new projected proton therapy facility and, as such, it may serve as a new source of comparison and validation for the international community, besides confirming the viability of the project from a radioprotection point of view.     

Transversal dose distribution optimization for laser-accelerated proton beam medical applications by means of Geant4

The main purpose of this paper is to quantitatively study the possibility of delivering dose distributions of clinical relevance with laser-driven proton beams. A Monte Carlo application has been developed with the Geant4 toolkit, simulating the ELIMED (MEDical and multidisciplinary application at ELI-Beamlines) transport and dosimetry beam line which is being currently installed at the ELI-Beamlines in Prague (CZ). The beam line will be used to perform irradiations for multidisciplinary studies, with the purpose of demonstrating the possible use of optically accelerated ion beams for therapeutic purposes. The ELIMED Geant4-based application, already validated against reference transport codes, accurately simulates each single element of the beam line, necessary to collect the accelerated beams and to select them in energy. Transversal dose distributions at the irradiation point have been studied and optimized to try to quantitatively answer the question if such kind of beam lines, and specifically the systems developed for ELIMED in Prague, will be actually able to transport ion beams not only for multidisciplinary applications, such as pitcher-catcher nuclear reactions (e.g. neutrons), PIXE analysis for cultural heritage and space radiation, but also for delivering dose patterns of clinical relevance in a future perspective of possible medical applications.     

Advancing simulations of biological materials: applications of coarse-grained models on graphics processing unit hardware

The timescales of biological processes, primarily those inherent to the molecular mechanisms of disease, are long (>μs) and involve complex interactions of systems consisting of many atoms (>10⁶). Simulating these systems requires an advanced computational approach, and as such, coarse-grained (CG) models have been developed and highly optimised for accelerator hardware, primarily graphics processing units (GPUs). In this review, I discuss the implementation of CG models for biologically relevant systems, and show how such models can be optimised and perform well on GPU-accelerated hardware. Several examples of GPU implementations of CG models for both molecular dynamics and Monte Carlo simulations on purely GPU and hybrid CPU/GPU architectures are presented. Both the hardware and algorithmic limitations of various models, which depend greatly on the application of interest, are discussed.     

Radiation damage to neuronal cells: Simulating the energy deposition and water radiolysis in a small neural network

Radiation damage to the central nervous system (CNS) has been an on-going challenge for the last decades primarily due to the issues of brain radiotherapy and radiation protection for astronauts during space travel. Although recent findings revealed a number of molecular mechanisms associated with radiation-induced impairments in behaviour and cognition, some uncertainties exist in the initial neuronal cell injury leading to the further development of CNS malfunction. The present study is focused on the investigation of early biological damage induced by ionizing radiations in a sample neural network by means of modelling physico-chemical processes occurring in the medium after exposure. For this purpose, the stochastic simulation of incident particle tracks and water radiation chemistry was performed in realistic neuron phantoms constructed using experimental data on cell morphology. The applied simulation technique is based on using Monte-Carlo processes of the Geant4-DNA toolkit. The calculations were made for proton, ¹²C, and ⁵⁶Fe particles of different energy within a relatively wide range of linear energy transfer values from a few to hundreds of keV/μm. The results indicate that the neuron morphology is an important factor determining the accumulation of microscopic radiation dose and water radiolysis products in neurons. The estimation of the radiolytic yields in neuronal cells suggests that the observed enhancement in the levels of reactive oxygen species may potentially lead to oxidative damage to neuronal components disrupting the normal communication between cells of the neural network.     

A structural analytic method on the phase space data of Linac 4 MV photons based on the real world

PurposeIt was given that the characteristics of the fluence distribution and the energy spectrum structure of 4MV photons on the Phase Space (PhSp) plane and a method to analyzing the characteristics.MethodsAfter the PhSp file of 4 MV photons was acquired by the method of Monte Carlo (MC) calculation, the photons recorded by PhSp file were grouped based on the energy bin, and it was analyzed that the spatial distribution and energy spectrum structure of the photons. The photons in each energy group were continually grouped to sub-files according to momentum bin, and the primary and scattered photons could be separated according to the character of the fluence distribution of the photons in the sub-files.ResultsThe energy of 4 MV beam is a continuous spectrum. The energy constituent on a pixel at different distances from the center point is different, and the average energy on the center axis of the field is the highest; The photons with 0–1.0 MeV had 42.6% of all; that with energy more than 3.0 MeV had 11.7%; greater than 4 MeV, just 1.5%. The primary and scattered photons were easy collected according to the distribution characteristics of sub-groups.ConclusionsThe work to acquire and analyze the PhSp file of the 4 MV beam is significant. 4 MV, 6 MV, 8 MV, 10 MV and 15 MV energy beams basically cover the beams of radiotherapy, and a database of the energy beams could be built for the MC related research of other scholars.     

Grazers and grass: Monte Carlo simulations

To illustrate the interplay between grazers and grass, we present a novel Monte Carlo model including grass-island growth, consumption of grass by grazers, and birth, migration and death of grazers. The rates of the former and three latter processes are assumed to depend on the environment so that the conventional mean-field approximation does not hold (in particular, the model takes into account that grass grows on the grass-island boundaries, and grazers are mobile and prefer to stay on the areas covered by grass). Due to the feedback between various processes, as expected, the model predicts stable regimes and irregular oscillations of the area of the grass islands and grazer population. The patterns observed are however different compared to those predicted by conventional Monte Carlo prey-predator models. Specifically, there is no tendency for grazers and grass to segregate. The mean-field version of the model is briefly discussed as well.     

Measurement-based model of a wide-bore CT scanner for Monte Carlo dosimetric calculations with GMCTdospp software

The aim of this work was to create a model of a wide-bore Siemens Somatom Sensation Open CT scanner for use with GMCTdospp, which is an EGSnrc-based software tool dedicated for Monte Carlo calculations of dose in CT examinations.The method was based on matching spectrum and filtration to half value layer and dose profile, and thus was similar to the method of Turner et al. (Med. Phys. 36, pp. 2154–2164). Input data on unfiltered beam spectra were taken from two sources: the TASMIP model and IPEM Report 78. Two sources of HVL data were also used, namely measurements and documentation. Dose profile along the fan-beam was measured with Gafchromic RTQA-1010 (QA+) film. Two-component model of filtration was assumed: bow-tie filter made of aluminum with 0.5 mm thickness on central axis, and flat filter made of one of four materials: aluminum, graphite, lead, or titanium.Good agreement between calculations and measurements was obtained for models based on the measured values of HVL. Doses calculated with GMCTdospp differed from the doses measured with pencil ion chamber placed in PMMA phantom by less than 5%, and root mean square difference for four tube potentials and three positions in the phantom did not exceed 2.5%. The differences for models based on HVL values from documentation exceeded 10%. Models based on TASMIP spectra and IPEM78 spectra performed equally well.     

Grid computing and molecular simulations: the vision of the eMinerals project

This paper discusses a number of aspects of using grid computing methods in support of molecular simulations, with examples drawn from the eMinerals project. A number of components for a useful grid infrastructure are discussed, including the integration of compute and data grids, automatic metadata capture from simulation studies, interoperability of data between simulation codes, management of data and data accessibility, management of jobs and workflow, and tools to support collaboration. Use of a grid infrastructure also brings certain challenges, which are discussed. These include making use of boundless computing resources, the necessary changes, and the need to be able to manage experimentation.     

Study of the effect of ceramic Ta2O5 nanoparticle distribution on cellular dose enhancement in a kilovoltage photon field

The application of nanoparticles (NPs) in radiotherapy is an increasingly attractive technique to improve clinical outcomes. The internalisation of NPs within the tumour cells enables an increased radiation dose to critical cellular structures. The purpose of this study is to investigate, by means of Geant4 simulations, the dose enhancement within a cell population irradiated with a 150 kVp photon field in the presence of a varying concentration of tantalum pentoxide (Ta₂O₅) NP aggregates, experimentally observed to form shells within tumour cells. This scenario is compared to the more traditionally simulated homogeneous solution of NP material in water with the same weight fraction of Ta₂O₅, as well as to a cell population without NPs present. The production of secondary electrons is enhanced by increased photoelectric effect interactions within the high-Z material and this is examined in terms of their kinetic energy spectra and linear energy transfer (LET) with various NP distributions compared to water. Our results indicate that the shell formation scenario limits the dose enhancement at 150 kVp. The underlying mechanism for this limit is discussed.     

Activation of Bax by joint action of tBid and mitochondrial outer membrane: Monte Carlo simulations

The mitochondrial pathway of apoptosis proceeds when molecules, such as cytochrome c, sequestered between the outer and inner mitochondrial membranes are released to the cytosol by mitochondrial outer membrane (MOM) permeabilization. Bax, a member of the Bcl-2 protein family, plays a pivotal role in mitochondrion-mediated apoptosis. In response to apoptotic stimuli, Bax integrates into the MOM, where it mediates the release of cytochrome c from the intermembrane space into the cytosol, leading to caspase activation and cell death. The pro-death action of Bax is regulated by interactions with both other prosurvival proteins, such as tBid, and the MOM, but the exact mechanisms remain largely unclear. Here, the mechanisms of integration of Bax into a model membrane mimicking the MOM were studied by Monte Carlo simulations preceded by a computer prediction of the docking of tBid with Bax. A novel model of Bax activation by tBid was predicted by the simulations. In this model, tBid binds to Bax at an interaction site formed by Bax helices α1, α2, α3 and α5 leading, due to interaction of the positively charged N-terminal fragment of tBid with anionic lipid headgroups, to Bax reorientation such that a hydrogen-bonded pair of residues, Asp98 and Ser184, is brought into close proximity with negatively charged lipid headgroups. The interaction with these headgroups destabilizes the hydrogen bond which results in the release of helix α9 from the Bax-binding groove, its insertion into the membrane, followed by insertion into the membrane of the α5–α6 helical hairpin. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Efficient procedure of preparation and properties of long uniform G4-DNA nanowires

Here we describe a novel and efficient procedure for preparation of long uniform G4-DNA wires. The procedure includes (i) enzymatic synthesis of double-stranded DNA molecules consisting of long (up to 10,000 bases), continuous G strands and chains of complementary (dC)20-oligonucleotides, poly(dG)-n(dC)20; (ii) size exclusion HPLC separation of the G strands from the (dC)20 oligonucleotides in 0.1M NaOH; and (iii) folding of the purified G strands into G4-DNA structures by lowering the pH to 7.0. We show by atomic force microscopy (AFM) that the preparation procedure yielded G4-DNA wires with a uniform morphology and a narrow length distribution. The correlation between the total amount of nucleotides in the G strands and the contour length of the G4-DNA molecules estimated by AFM suggests monomolecular folding of the G strands into quadruplex structures. The folding takes place either in the presence or in the absence of stabilizing ions (K+ or Na+). The addition of these cations leads to a dramatic change in the circular dichroism spectrum of the G4-DNA.